Single-cell immune multi-omics and repertoire analyses in pancreatic ductal adenocarcinoma reveal differential immunosuppressive mechanisms within different tumour microenvironments

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis. Understanding the multiple mechanisms by which the tumour evades immune control, and how these mechanisms may be disrupted is critical to developing targeted immunotherapies. Previous studies have shown that higher lymphocyte infiltration is associated with better survival, and here we investigated what mediates these differences. We performed a comprehensive analysis of PDAC-associated immune cells using single cell multi-omics coupled with re-analysis of public PDAC scRNA-seq datasets. We introduce novel single-cell and repertoire analyses that have uncoupled diverse roles and contributions of various immune cell populations within different tumour microenvironments (TMEs). They revealed clear distinctions in the clonal characteristics among different patient groups, provided valuable insights into the mechanisms of immune cell migration and tissue adaptation underlying these disparities. These results point to differential CD4 polarisation of intra-tumoural T cells, differential B cell differentiation, GC reactions, antigen presentation pathways, and distinct cell-cell communication between the myeloid-enriched and adaptive-enriched groups. Overall, we identified two major distinct themes for future immune intervention within PDAC patients between those with higher adaptive versus myeloid immune cell infiltration.

Manipulating regulatory T cells: is it the key to unlocking effective immunotherapy for pancreatic ductal adenocarcinoma?

“…Initial efforts utilised autochthonous murine models of PDAC: Kras LSL-G12D/+ ; Pdx-1-Cre (KC) and Kras LSL-G12D/+ ; Trp53 LSL-R172H/+ ; Pdx-1-Cre (KPC), which recapitulate features of the human disease ( 12 , 13 ). More recent analyses have profiled the immune landscape of patient-derived tumour samples, facilitated by advances in single-cell multi-omic technologies ( 14 – 16 ).…”

“…This approach can be optimised with consideration of the relative abundance and distribution of specific F c γRs on local effector cells; indeed, the engineering of anti-CTLA-4 mAbs in this manner has been shown to increase therapeutic activity in tumour-bearing mice ( 59 , 62 ). Therefore, it is important that studies have identified intratumoral populations of F c γRIIIA (CD16)-expressing natural killer and myeloid cells in human PDAC ( 14 – 16 ). Moreover, Agenus recently initiated a phase I/II trial to investigate botensilimab – an F c -engineered anti-CTLA-4 mAb with enhanced affinity for F c γRIIIA – in metastatic PDAC patients (NCT05630183).…”